tbuckley/cabot-search huggingface dataset:
Abstract B056: Wild-type RAS/MAPK signaling complexes mediate adaptive resistance to KRAS inhibition in PDAC
Authors: Xiangyu Ge, Christian F. Ruiz, Wenxue Li, Yanixa Quiñones-Avilés, Mandar Deepak Muzumdar
Journal: Cancer Research (2022)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy and predicted to be the second most common cause of death in the US within the next decade. A striking hallmark of PDAC is the presence of activating KRAS mutations in &amp;gt;90% of all cases. Studies in animal models and cell lines have suggested that oncogenic KRAS is important for both the initiation and progression of PDAC, making KRAS an attractive target for therapy. Recent FDA approvals of KRAS mutant-specific inhibitors has advanced the clinical treatment of patients with cancers harboring mutant KRAS, yet resistance inevitably occurs through both genetic (second-site mutations, bypass pathways) and non-genetic (adaptive) mechanisms. Elucidating the adaptive mechanisms by which cancers evade KRAS inhibition in PDAC will enable the development of more efficacious and durable combinatorial therapeutic strategies with emerging KRAS inhibitors. To address this gap in knowledge, we used CRISPR/Cas-mediated gene knockout technology to model KRAS inhibition in PDAC and found that KRAS is dispensable in a subset of human and mouse PDAC cells, arguing that KRAS is not absolutely required for tumor maintenance. KRAS-deficient cells showed enhanced sensitivity to phosphoinositide 3-kinase (PI3K) inhibitors (PI3Ki), which functioned not only to block canonical AKT signaling but also, unexpectedly, to suppress mitogen-activated protein kinase (MAPK) signaling through rapid attenuation of wild-type RAS/MAPK activity in single cells. Importantly, we confirmed this novel regulatory role of PI3K in mediating RAS/MAPK activity across multiple wild-type KRAS-expressing malignant and non-malignant cell lines, supporting the generalizability of this signaling axis. Furthermore, unbiased proximity protein labeling (BioID) revealed that PI3K inhibition reduces the interaction of KRAS with canonical regulators, effectors, and scaffolds in RAS/MAPK signaling. Parallel genome-wide CRISPR screens comparing KRAS intact and isogenic KRAS-deficient PDAC cells revealed specific RAS/MAPK scaffold/docking proteins as essential for PDAC cell fitness following KRAS ablation. Together, our work sheds new light into the regulatory role of PI3K in wild-type RAS/MAPK signaling, highlights the importance of functional wild-type RAS/MAPK signaling complexes in adaptive resistance to KRAS inhibition, and nominates potential therapeutic targets to overcome resistance to KRAS inhibition in PDAC and possibly other KRAS mutant cancers. Citation Format: Xiangyu Ge, Christian F. Ruiz, Wenxue Li, Yanixa Quiñones-Avilés, Mandar Deepak Muzumdar. Wild-type RAS/MAPK signaling complexes mediate adaptive resistance to KRAS inhibition in PDAC [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr B056.
Abstract C018: Co-activation of myeloid signaling pathways for pancreatic cancer immunotherapy
Authors: Max M. Wattenberg, Heather Coho, Veronica M. Herrera, Kathleen Graham, Meredith L. Stone, Yuqing Xue, Renee B. Chang, Christopher Cassella, Mingen Liu, Shaanti Choi-Bose, Stacy K. Thomas, Hana Choi, Yan Li, Lauren Melendez, Michael Giannone, Nandita Bose, Gregory L. Beatty
Journal: Cancer Research (2022)

Abstract Pancreatic ductal adenocarcinoma (PDA) is characterized by a robust myeloid cell infiltrate. Although myeloid cells in PDA most commonly associate with immunosuppression, they also show plasticity and possess the capacity to engage productive anti-tumor immunity, thereby providing a potential therapeutic vulnerability. Here, we show that distinct myeloid cell subsets infiltrating human PDA express non-redundant activating receptors. Among the most highly expressed receptors was the pattern recognition receptor CLEC7A, which was expressed by macrophages, monocytes, and immature myeloid cells. In contrast, the TNF superfamily member CD40, was expressed by dendritic cells (DC) and SPP1+ macrophages. We hypothesized that combinatory targeting of myeloid activating receptors might be needed to restore productive immunosurveillance in PDA. In immune checkpoint blockade-resistant mouse models of PDA, pharmacologic activation of CLEC7A, using beta glucan (BG) therapy was associated with upregulation of the CXCL2/3-CXCR2 axis and triggered increases in intra-tumoral macrophages and granulocytes. Conversely, CD40 agonist therapy induced activity of the CXCL9-CXCR3 axis and drove conventional DC type 1-dependent infiltration of CD4+ and CD8+ T cells into tumors. Neither myeloid agonist alone, though, was sufficient to trigger durable anti-tumor immunity. By contrast, induction of both myeloid and lymphoid immunosurveillance by co-activation of CLEC7A/CD40 pathways caused tumor eradication, durable tumor control and T cell dependent immunological memory. Depletion of CSF1R+ myeloid cells or T cells significantly reduced the anti-tumor activity of treatment thereby highlighting the cooperativity of innate and adaptive immunity for anti-tumor activity. Moreover, the efficacy of CLEC7A and CD40 co-activation was independent of immune checkpoint blockade. Thus, beyond inhibitory checkpoint molecules on T cells, combinatory activation of non-redundant myeloid signaling pathways can be leveraged to trigger durable anti-tumor immunity, suggesting a new immunotherapy paradigm. A clinical trial of CLEC7A and CD40 agonist therapy for the treatment of patients with PDA is under development. Citation Format: Max M. Wattenberg, Heather Coho, Veronica M. Herrera, Kathleen Graham, Meredith L. Stone, Yuqing Xue, Renee B. Chang, Christopher Cassella, Mingen Liu, Shaanti Choi-Bose, Stacy K. Thomas, Hana Choi, Yan Li, Lauren Melendez, Michael Giannone, Nandita Bose, Gregory L. Beatty. Co-activation of myeloid signaling pathways for pancreatic cancer immunotherapy [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr C018.
Abstract C049: WT1+ cancer-associated fibroblasts promote pancreatic cancer growth
Authors: Allison Bischoff, Yaqing Zhang, Wei Yan, Kristee Brown, Wenting Du, Marina Pasca di Magliano
Journal: Cancer Research (2022)

Abstract Pancreatic ductal adenocarcinoma (PDA) is characterized by dense, fibro-inflammatory stroma that is established in early pathogenesis. Cancer-associated fibroblasts (CAFs) make up a significant proportion of the tumor microenvironment and represent a heterogeneous cell population that play both tumor-promoting and tumor-restricting roles. Despite their dramatic expansion in PDA pathogenesis, it is still unclear what cells in the normal pancreas give rise to these CAFs. Lineage-tracing experiments have previously identified pancreatic stellate cells, mesothelial, and tissue-resident fibroblasts as progenitors to subsets of CAFs. In this research, we firstly pulse-labeled cells expressing the mesothelial and fibroblast marker Wilms tumor 1 (WT1) in the normal pancreas of WT1CreERT;R26tdTomato mice and used an orthotopic model of PDA to trace their contribution to the PDA tumor microenvironment. We found WT1+ cells in the normal pancreas expanded to comprise a significant proportion of PDA CAFs according to immunofluorescence. Based upon single-cell RNA-sequencing (scRNA-seq), these WT1+ precursors represent an endogenous pancreatic fibroblast population similar to previously characterized universal adventitial fibroblasts (Pi16+, Dpp4+). To determine the role of WT1 in established PDA, we labeled WT1+ cells following orthotopic tumor implantation into WT1CreERT;R26tdTomato mice, and scRNA-seq analysis revealed that both inflammatory CAFs (iCAFs) and myofibroblastic CAFs (MyCAFs) express WT1. Notably, iCAFs had higher relative expression of WT1+. Additionally, we depleted WT1+ cells with diphtheria toxin from orthotopic tumors established in WT1CreERT;R26tdTomato/iDTR mice. We found depletion of WT1+ cells reduced orthotopic tumor growth, and depleted fibroblasts from the PDA tumor microenvironment. These findings implicate WT1 as a promising lineage tracing marker for a subset of pancreatic fibroblasts and demonstrates a pro-tumorigenic role of WT1+ fibroblasts in PDA. Citation Format: Allison Bischoff, Yaqing Zhang, Wei Yan, Kristee Brown, Wenting Du, Marina Pasca di Magliano. WT1+ cancer-associated fibroblasts promote pancreatic cancer growth [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr C049.
Breakthrough infections in MPN-COVID vaccinated patients
Authors: Tiziano Barbui, Alessandra Carobbio, Arianna Ghirardi, Alessandra Iurlo, Valerio De Stefano, Marta Anna Sobas, Elisa Rumi, Elena Maria Elli, Francesca Lunghi, Mercedes Gasior Kabat, Beatriz Cuevas, Paola Guglielmelli, Massimiliano Bonifacio, Monia Marchetti, Alberto Alvarez-Larran, Laura Fox, Marta Bellini, Rosa Daffini, Giulia Benevolo, Gonzalo Carreno-Tarragona, Andrea Patriarca, Haifa Kathrin Al-Ali, Maria Marcio Miguel Andrade-Campos, Francesca Palandri, Claire Harrison, Maria Angeles Foncillas, Santiago Osorio, Steffen Koschmieder, Elena Magro Mazo, Jean-Jacques Kiladjian, Estefanía Bolaños Calderón, Florian H. Heidel, Keina Quiroz Cervantes, Martin Griesshammer, Valentin Garcia-Gutierrez, Alberto Marin Sanchez, Juan Carlos Hernandez-Boluda, Emma Lopez Abadia, Giuseppe Carli, Miguel Sagues Serrano, Rajko Kusec, Blanca Xicoy Cirici, Margarita Guenova, Begona Navas Elorza, Anna Angona, Edyta Cichocka, Anna Kulikowska de Nałęcz, Daniele Cattaneo, Cristina Bucelli, Silvia Betti, Oscar Borsani, Fabrizio Cavalca, Sara Carbonell, Natalia Curto-Garcia, Lina Benajiba, Alessandro Rambaldi, Alessandro Maria Vannucchi
Journal: Blood Cancer Journal (2022)
Abstract B013: PP2A regulated macropinocytosis and therapeutic vulnerabilities in pancreatic cancer
Authors: Garima Baral, Claire M. Pfeffer, Brittany L. Allen-Petersen, Indiraa Doraivel
Journal: Cancer Research (2022)

Abstract Pancreatic Ductal Adenocarcinoma (PDAC) is the fourth leading cause of cancer related deaths in the US, with the lowest five-year survival rate of all cancers. Nutrients in the PDAC microenvironment are commonly depleted, with the vital amino acid glutamine among the most deficient metabolites. In an attempt to circumvent this deprivation, PDAC cells initiate KRAS dependent macropinocytosis, an actin-driven nutrient scavenging pathway. Macropinocytosis allows cells to replenish the nutrients required for proliferation and survival. As glutamine is essential for PDAC cell survival, therapeutic inhibition of macropinocytosis represents a novel strategy to suppress nutrient acquisition and drive cell death in PDAC. Protein phosphatase 2A (PP2A) is a heterotrimeric Serine/Threonine phosphatase known to inhibit downstream targets of the KRAS signaling cascade and is implicated in macropinocytosis regulation. We demonstrate that pharmacological activation of PDAC cell lines with the small molecule activator of PP2A, DT061, leads to significant accumulation of intracellular vesicles. Therefore, we hypothesize that PP2A activation results in methuosis, a non-apoptotic cell death process driven by aberrant macropinocytosis. Using high molecular weight TMR-Dextran, we confirmed that these vesicles are macropinosomes. PP2A activation prevented the colocalization of macropinosomes with lysosomes, likely limiting the nutrients supply to PDAC cells. RNA sequencing analysis showed that glutamine deprivation genes are significantly enriched with acute activation of PP2A, and the oxidative phosphorylation pathway was observed to be significantly inhibited. Further, combination of DT061 with Glutamine transport inhibitor V-9302 significantly inhibits the survival of PDAC cells. Together, these findings indicate that activation of PP2A in late stage PDAC promotes aberrant macropinocytosis and establishes a novel role of PP2A in nutrient scavenging and cell death. These pathways can be further exploited to identify potential therapeutics in PDAC. Citation Format: Garima Baral, Claire M. Pfeffer, Brittany L. Allen-Petersen, Indiraa Doraivel. PP2A regulated macropinocytosis and therapeutic vulnerabilities in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr B013.
Characteristics of measurable residual disease assessment in myeloma: a review of clinical trials from 2015–2020
Authors: Oliver Van Oekelen, Nicole Birrer, William Wesson, Vincent L. Galate, Edward R. Scheffer Cliff, Aaron M. Goodman, Al-Ola Abdallah, Rajshekhar Chakraborty, Vinay Prasad, Ghulam Rehman Mohyuddin
Journal: Blood Cancer Journal (2022)
Abstract PR018: Hypoxia synergizes with IL1 to promote an inflammatory fibroblast state in the pancreatic tumor microenvironment
Authors: Simon Schwoerer, Manon Ros, Kaloyan Tsanov, Francesco Cimino, Scott Lowe, Carlos Carmona-Fontaine, Craig Thompson
Journal: Cancer Research (2022)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is characterized by a prominent desmoplastic response created by cancer-associated fibroblasts (CAFs) that can acquire both tumor-promoting and -restraining functions. Recently, transcriptionally distinct subpopulations of CAFs have been identified in PDAC including tumor-restraining myofibroblastic CAFs (myCAFs) producing extracellular matrix and tumor-promoting inflammatory CAFs (iCAFs) secreting cytokines. While CAF heterogeneity can be driven in part by growth factor and cytokine gradients, other factors involved in shaping the CAF state in PDAC are largely unknown. Identifying and targeting such factors may help to drive CAFs from tumor-promoting into tumor-suppressive states. Hypoxia is a major environmental factor in the PDAC tumor microenvironment but its role in CAF plasticity is unknown. In this study, we use KPC organoid orthotopic transplantation and co-culture models to investigate the role of hypoxia in regulating the CAF state and functions. We find that iCAFs display a hypoxic gene expression and biochemical profile in vivo and are enriched in hypoxic regions of PDAC tumors. Hypoxia leads to acquisition of an inflammatory gene expression signature in fibroblasts and synergizes with cancer cell-derived IL1 to promote an iCAF phenotype in a HIF-1α dependent fashion. Furthermore, we show in PDAC organoid co-culture models that HIF-1α stabilization is sufficient to induce an iCAF phenotype in pancreatic stellate cells and to promote PDAC tumor growth in vivo in the absence of hypoxia. These data indicate Citation Format: Simon Schwoerer, Manon Ros, Kaloyan Tsanov, Francesco Cimino, Scott Lowe, Carlos Carmona-Fontaine, Craig Thompson. Hypoxia synergizes with IL1 to promote an inflammatory fibroblast state in the pancreatic tumor microenvironment [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr PR018.
Joint consensus statement on the vaccination of adult and paediatric haematopoietic stem cell transplant recipients: Prepared on behalf of the British society of blood and marrow transplantation and cellular therapy (BSBMTCT), the Children's cancer and Leukaemia Group (CCLG), and British Infection Association (BIA)
Authors: PDE Miller, SR Patel, R Skinner, F Dignan, A Richter, K Jeffery, A Khan, PT Heath, A Clark, K Orchard, JA Snowden, TI de Silva
Journal: Journal of Infection (2022)

Haematopoietic stem cell transplant (HSCT) recipients have deficiencies in their adaptive immunity against vaccine preventable diseases. National and International guidance recommends that HSCT recipients are considered 'never vaccinated' and offered a comprehensive course of revaccination. This position statement aims to draw upon the current evidence base and existing guidelines, and align this with national vaccine availability and licensing considerations in order to recommend a pragmatic and standardised re-vaccination schedule for adult and paediatric HSCT recipients in the UK.
Abstract B009: Multi-omics analysis of glutathione S-transferase P1 (GSTP1) knockdown model suggests role in pancreatic ductal adenocarcinoma (PDAC) cell metabolism
Authors: Jenna Duttenhefner, Katie M. Reindl
Journal: Cancer Research (2022)

Abstract GSTP1 belongs to a large family of detoxification enzymes essential for cellular homeostasis in healthy cells. GSTP1 is overexpressed in many cancers and is associated with poor survival in PDAC patients. Studies in glioblastoma and breast cancer have suggested crucial roles of GST family members in metabolism through increased lactate dehydrogenase A and increased GAPDH activity, respectively. The mechanisms underlying the action of GSTP1 in PDAC metabolism and cell proliferation are not well studied. To begin characterizing the diverse functions of GSTP1 in cancer cells, we knocked down GSTP1 expression in three different PDAC cell lines. We revealed unique changes in the global transcriptomic, proteomic, and metabolomic signatures associated with GSTP1 knockdown compared to control cells through multi-omics techniques, real-time ATP production assays, and comprehensive hydrophilic metabolite and phospholipid panels. Through preliminary transcriptomic and proteomic analyses, we found 461 genes and 57 proteins differentially expressed in our GSTP1 knockdown MIA PaCa-2 cells. Among these, 41 were similarly upregulated or downregulated at the mRNA and protein levels. Pathway analysis of these changes revealed profound effects on energy production and lipid metabolism in GSTP1 knockdown cells. Hydrophilic metabolite and phospholipid panels and real-time ATP production assays supported our findings. Our results indicate that GSTP1 knockdown may directly influence mitochondrial dysfunction and lipid peroxidation pathways through associated reductions in ALDH7A1, GLUT3, and SLC7A11 levels. Continued research to further elucidate precise mechanisms and understand GSTP1’s role in driving cancer cell metabolism will aid in establishing GSTP1 targeting as a therapeutic opportunity for PDAC treatment. Citation Format: Jenna Duttenhefner, Katie M. Reindl. Multi-omics analysis of glutathione S-transferase P1 (GSTP1) knockdown model suggests role in pancreatic ductal adenocarcinoma (PDAC) cell metabolism [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr B009.
Abstract C077: Evidence for a tumoral temperature driven chemoresistance pathway in pancreatic cancer
Authors: Vincent de Laat, Halit Topal, Jonas Dehairs, Xander Spotbeen, Ali Talebi, Frank Vanderhoydonc, Tessa Ostyn, Tania Roskams, Baki Topal, Johan Swinnen
Journal: Cancer Research (2022)

Abstract Tumor growth is inevitably accompanied by changes in the tumor-microenvironment to which cancer cells have to adapt in order to thrive. Alterations in metabolism and blood perfusion of solid tumors have been suggested to drive a spontaneous increase in tumoral temperature. However, it is currently unknown if this phenomenon affects cancer biology. We found increased temperature in human pancreatic ductal adenocarcinoma (PDAC) tumors. By mimicking this observation in PDAC cell lines, we found that cancer cells adapt to tumoral temperature by altering the cellular lipidome and accordingly evade ferroptosis, a lipid-dependent form of cell death. We found evidence that tumoral temperature-induced ferroptosis evasion depends on p38-MAPK deactivation and ultimately drives resistance to the chemotherapeutic drug gemcitabine. Collectively, our findings suggest a direct role for p38-dependend ferroptosis evasion in gemcitabine resistance, and we identify tumoral temperature as a pathophysiological driver of this process. Our discovery unveils temperature as an unexplored hallmark of the tumor-microenvironment. Citation Format: Vincent de Laat, Halit Topal, Jonas Dehairs, Xander Spotbeen, Ali Talebi, Frank Vanderhoydonc, Tessa Ostyn, Tania Roskams, Baki Topal, Johan Swinnen. Evidence for a tumoral temperature driven chemoresistance pathway in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr C077.
Abstract B046: Restricted cellular plasticity of human pancreatic ductal cells into a pluripotent state
Authors: Dmytro Grygoryev, Taelor Ekstrom, Jason M. Link, Rosalie C. Sears, Jungsun Kim
Journal: Cancer Research (2022)

Abstract Cancer cells undergo plasticity against stress for the survival of the fittest. Pancreatic ductal adenocarcinoma (PDAC) also shows intratumoral transcriptional heterogeneity with cell plasticity, which correlates with phenotypical aggressiveness and therapeutic resistance. Cell fates are determined by master transcription factors (TFs, also called “pioneer factors”) and their co-factors by opening up chromatin and establishing competence for gene expression specific to each cell type during normal development. Force expression of various combinations of pioneer factors can switch cell fate into other lineages, including induced pluripotent stem cells (“iPSC”). Since pluripotent stem cells do not have the cancer hallmarks of uncontrolled cell growth and migration, hypothetically, a fully reprogrammed cancer iPSC should regain gene programs to control these hallmarks of cancer. Thus, we and others have reprogrammed cancer cells into pluripotent stem cell-like cells by introducing pluripotent pioneer factors. However, intriguingly, despite the nature of the high plasticity of cancer, complete reprogramming of cancers to a pluripotent state is impeded in most cases, enabling us to study and model cancer progression. Our further studies confirm that, upon reprogramming, most PDAC cells lose the original PDAC phenotypes to some extent but remain in plasticity states during reprogramming. Herein, we further update on our efforts to optimize the reprogramming of normal pancreatic ductal epithelial cell line (PDEC) and PDAC derived from patients through the Sendai virus, which can most robustly transfer genes regardless of cell types. While control cells (e.g., acinar cells and fibroblast) were fully reprogrammed into iPSC cells, both PDEC and PDAC were impeded from being fully reprogrammed into pluripotency. Intriguingly, a subset of normal PDEC cells as well as some PDAC cell acquired a “partial reprogramming marker” upon reprogramming, suggesting that PDEC cells are stalled in early developmental states. Therefore, we now conclude that normal and cancerous pancreatic ductal cell states have an intrinsic mechanism that blocks complete reprogramming into a pluripotent state, and the oncogenic pathway is poised for activation, despite the nature of the high plasticity of PDAC. Identifying the factors responsible for maintaining this impenetrable cancer chromatin landscape is ideal for nominating therapeutic targets for intercepting PDAC plasticity. This work is supported by OHSU/CEDAR project award 68182-939-000. Citation Format: Dmytro Grygoryev, Taelor Ekstrom, Jason M. Link, Rosalie C. Sears, Jungsun Kim. Restricted cellular plasticity of human pancreatic ductal cells into a pluripotent state [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr B046.